Creating Longer-Lasting Prophylactic Therapy

Creating Longer-Lasting Prophylactic Therapy

Although prophylactic factor replacement therapy in people with severe hemophilia significantly reduces the risk of bleeding, it is mainly hampered by the short duration of effectiveness (half-life) of current replacement factors. Scientists face many challenges when trying to improve treatments for hemophilia. They are trying to make factor replacement therapy last longer in the human body so that people with this disease need infusions less frequently, to make treatments that do not result in inhibitor development, to make infusion methods safer, and to supply treatment—especially prophylactic therapy—at lower cost.

A-LONG study. As an important step in this direction, scientists have attached rFVIII to a fusion protein (Fc) to make a factor replacement known as rFVIIIFc that keeps working in the bloodstream for as long as 2 weeks.

In the A-LONG study, a research team studied 165 males with severe hemophilia A who were at least 12 years of age. The patients were divided up into three groups. One group received prophylactic rFVIIIFc treatment according to the results of blood tests, the second group received a constant dose of rFVIIIFc once a week, and the third group received rFVIIIFc as needed for bleeding. Most of the patients in the first group could go without treatment for 3½ days or longer, and one third of them eventually needed to be treated with rFVIIIFc every 5 days during the last months of the study. There were an average of 1.6 bleeding episodes in the first group, 3.6 in the second group, and 33.6 in the third group. Just one injection of rFVIIIFc stopped over 85% of the bleeding episodes. Importantly, none of the participants in this study developed inhibitors to rFVIIIFc, and side effects were similar to those expected with any group of people with hemophilia A. Treated individuals who needed major surgery had good or excellent bleeding control.

B-LONG study. Children and adults with hemophilia B who are being treated prophylactically with plasma-derived or recombinant factor IX usually require three infusions a week or every other day. Reducing the frequency of infusions needed by using a longer-acting replacement factor instead of FIX would greatly reduce the burden of prophylactic therapy on those with hemophilia B.

In the B-LONG study, 123 males with severe hemophilia B were given a new long-lasting formulation of factor IX known as recombinant factor IX Fc fusion protein (rFIXFc). All of the patients were 12 years of age and older, had been receiving prophylactic therapy with factor IX for at least 100 days before entering the study, and had not developed any antibody inhibitors to factor IX that would have lessened its effectiveness. The researchers divided the patients into four groups:

  • Group 1 received rFIXFc regularly once a week (weekly prophylaxis group).
  • Group 2 were given rFIXFc every 10 days or longer, the interval between doses being determined individually (intermittent prophylaxis group).
  • Group 3 were treated with rFIXFc on demand, only when they began bleeding.
  • Group 4 were given rFIXFc before, during, and after surgery.

Group 1, those who received weekly prophylaxis treatment, experienced an 83% reduction in the yearly rate of bleeding compared with those who received on-demand treatment only (group 3). Patients in the intermittent prophylaxis group (group 2) fared even better, with a 92% reduction in the yearly rate of bleeding compared with patients treated on demand. Half of the patients receiving individualized prophylactic therapy with rFIXFc could go more than two weeks between doses and still be adequately protected against bleeding. In the group receiving weekly prophylaxis, researchers compared yearly bleeding rates, adverse events, and development of inhibitors between adolescents (12 to 17 years old) and adults (18 to 65 years old). The bodies of adolescents and adults used and broke down rFIXFc similarly. Yearly bleeding rates were comparable, and both the adolescents and adults in this group had fewer bleeding episodes per year than patients receiving rFIXFc on demand.

What Does This Mean to People With Hemophilia?

The use of rFVIIIFc showed good results in the first large clinical study to test it in people with hemophilia A. So far, researchers believe that it may be as safe and effective as the recombinant factor therapy now being used.

Recent studies of how a new, long-acting recombinant factor IX replacement factor (rFIXFc) is processed and eliminated from the body, along with the results of the B-LONG study, suggest that people with severe hemophilia B can be protected against bleeding episodes by receiving rFIXFc once a week or every 10 days. In late March, 2014, the US Food and Drug Administration approved the use of this long-acting replacement factor for controlling and preventing bleeding episodes in people with hemophilia B.

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